The goal of this five-year mentored clinical scientist development award is to secure for the applicant the intensive training and intellectual, scientific and educational environment requisite for development as a successful, independent physician-scientist. To this end, we propose an integrated program of research and study designed to elucidate the mechanisms of transformation by translocations of the mixed lineage leukemia gene (MLL, HRX, ALL-1) and to develop models of MLL-mediated leukemia. Despite intensive study and investigation, it remains unclear as to how MLL fusion proteins participate in leukemongenesis. MLL fusion proteins are the products of reciprocal translocation events where the MLL gene on chromosome 11q23 is combined with over 30 different translocation partners resulting in lymphoid, myeloid and therapy-related leukemia's. Presumably the transforming effects of MLL fusion proteins are mediated through transcriptional deregulation, a gain of function activity contributed by the translocation partner. However, the remarkable number of translocation partners and the lack of homology among them have made it difficult to explain how they contribute to the oncogenic function of MLL. Emerging evidence suggests that transformation may be mediated through dimerization/oligomerization of truncated MLL. This model is attractive because it supplies a unifying hypothesis for the function of diverse MLL fusion proteins as well as exon duplicated forms of MLL that occur in some myeloid leukemias, and suggests a possible target for therapeutic intervention. The proposed research will aim to determine if dimerization or higher order oligomerization constitutes the mechanism of transformation by MLL fusion proteins. Additionally, we seek to establish a model of ALL using murine fetal liver retrovirally transduced with MLL-AF4, which is associated with infant ALL and for which appropriate animal models are lacking. Finally, we will establish a NOD/SCID model of MLL-mediated leukemia using human hematopoietic cells retrovirally transduced with bona fide MLL fusion proteins to further explore the mechanisms of transformation and to facilitate the future development of mechanism-based therapy.